title: Aurora A kinase regulates mammary epithelial cell fate by determining mitotic spindle orientation in a Notch-dependent manner.
abstract: Cell fate determination in the progeny of mammary epithelial stem/progenitor cells remains poorly understood. Here, we have examined the role of the mitotic kinase Aurora A (AURKA) in regulating the balance between basal and luminal mammary lineages. We find that AURKA is highly expressed in basal stem cells and, to a lesser extent, in luminal progenitors. Wild-type AURKA expression promoted luminal cell fate, but expression of an S155R mutant reduced proliferation, promoted basal fate, and inhibited serial transplantation. The mechanism involved regulation of mitotic spindle orientation by AURKA and the positioning of daughter cells after division. Remarkably, this was NOTCH dependent, as NOTCH inhibitor blocked the effect of wild-type AURKA expression on spindle orientation and instead mimicked the effect of the S155R mutant. These findings directly link AURKA, NOTCH signaling, and mitotic spindle orientation and suggest a mechanism for regulating the balance between luminal and basal lineages in the mammary gland.
authors.affiliation: Division of Breast Cancer Research, Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Regan
authors.forename: Tony
authors.initials: T
authors.lastname: Sourisseau
authors.forename: Kelly
authors.initials: K
authors.lastname: Soady
authors.forename: Howard
authors.initials: H
authors.lastname: Kendrick
authors.forename: Afshan
authors.initials: A
authors.lastname: McCarthy
authors.forename: Chan
authors.initials: C
authors.lastname: Tang
authors.forename: Keith
authors.initials: K
authors.lastname: Brennan
authors.forename: Spiros
authors.initials: S
authors.lastname: Linardopoulos
authors.forename: Donald E
authors.initials: DE
authors.lastname: White
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Smalley
mesh_terms: D053687:Adult Stem Cells / Q000166:cytology / Q000378:metabolism; D000818:Animals; D064096:Aurora Kinase A / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D005260:Female; D008321:Mammary Glands, Animal / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism; D011485:Protein Binding; D051881:Receptor, Notch1 / Q000378:metabolism*; D008941:Spindle Apparatus / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D008869:Microtubule-Associated Proteins; C497762:Notch1 protein, mouse; D009687:Nuclear Proteins; D051881:Receptor, Notch1; C572046:TPX2 protein, mouse; C576918:Aurka protein, mouse; D064096:Aurora Kinase A